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Thymoquinone Inhibit M2 Macrophage Polarization in Rat Infected with Mycobacterium tuberculosis

E Olivianto1*, A T Endharti2, S Santoso3, K Handono4, HMS C Kusuma5

1Doctoral Program Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

2Department of Parasitology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

3Department of Microbiology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

4Department of Clinical Pathology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

5Department of Child Health, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

*Email: [email protected]

ABSTRACT

Thymoquinonehas been known to have anti-inflammatory effect in diseases. However, its effect on macrophage polarization in M.

tuberculosis infection had not been studied. This research aimed to study the effect of thymoquinone on lung macrophages and its ability to inhibit M2 polarization in M. tuberculosis infection. Five groups of each five Rattus norvegicus rats were infected with M.

tuberculosis, except those in negative control group. Three groups were treated with thymoquinone 25, 50 and 75 mg/kg body weight, respectively; leaving one group as positive control. At day 21, the rats were killed and lung tissues were prepared in slides.

Immunohistochemistry staining was performed using mouse CD68 and CD163 antibodies. The stained macrophages were counted using a digital microscope.CD163 macrophages were significantly increased after M. tuberculosis infection. However, CD68 and CD68 to CD163 ratio were not significantly changed. Low dose (25mg/kg BW) of thymoquinone significantly decreased CD163 macrophages. Thymoquinone at dose of 50 mg/kg BW significantly increased CD68 macrophages. The CD68 to CD163 macrophages ratio was increased at lower dose (25-50 mg/kg BW) of thymoquinone group compared to positive control. We conclude thatthymoquinone can inhibit M2 polarization of lung macrophage of rat infected with M. tuberculosis.

Keywords: Alveolar macrophage;Nigella sativa; tuberculosis.

Introduction

Tuberculosis (TB) is still a problem worldwide. About 10 million people suffered from TB disease and 1.4 milliondied from TB in 2019(WHO, 2020). Although the history of TB drug development goes back more than 50 years ago, there are not many drug regimens currently used. Medicines in the form of a fixed drug combination (FDC) containing isoniazid, rifampicin, pyrazinamide, and ethambutol, are standard regimens for TB therapy. The emergence of multidrug resistant strains (MDR) necessitated the use of other second-line anti-TB drugs, which were actually reused old drugs. These drugs target the causative germ, Mycobacterium tuberculosis, as their target of action(Zumla et al., 2015).

So far, many host targeted immunomodulatory drugs have been studied to aid standard TB treatment. The administration of IL-2, IL-12, IFN-ɣ and several other recombinant effector cytokines can enhance the Th1 immune response in M. tuberculosis infection, while otherimmuno- modulators such as thalidomide, etanercept and corticosteroids act to suppress the immune response. Mycobacterium vaccae, high doses of antibodies and DNA vaccines have a role in increasing the Th1 immune response while suppressing the Th2 immune response(Guo and Zhao, 2012).

In the pathogenesis of TB, alveolar macrophagesare the first to encounter and play an important role in phagocyte and killing M.tuberculosis in the phagolysosomes. The activation of macrophages is induced by Th1 lymphocytes which produce IFN-to stimulatephagolysosome fusion and oxidative burstwithin macrophages. Unfortunately, M. tuberculosis has the abilities to circumvent the eradication mechanism within these macrophages. One of them is its ability to shift Th1/Th2 balance towards Th2 phenotype of immune response, thereby affecting the macrophage phenotype from M1 to M2. The initially M1 macrophage polarization, which promote granuloma formation and has bacterial killing activity, will shift to M2 polarization as the infection-induced inflammation increased. This will prevent M.tuberculosis from being eradicated within the macrophage and instead surviving in this phagocytic cell(Huang et al., 2015; Khan et al., 2019).

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Several herbal ingredients have been shown to have immunomodulating effects in various diseases.

One of them is Nigella sativa which for centuries has been traditionally used in the treatment of various diseases. Recent research has proven the effects of Nigella sativa and its active ingredient, thymoquinone, in various allergic, cancer, degenerative and even infectious diseases.

Thymoquinone has already known to have potential therapeutic effect on several diseases. Studies showed that this compound has anti-oxidant, anti-inflammatory and immunomodulator effects. It has also been demonstrated that thymoquinone may have anti-microbialand anti- tuberculareffect(Darakhshan et al., 2015; Dey et al., 2014; Randhawa, 2011).So far, there have been no research studied the immunomodulating effects of thymoquinone on TB disease, especially its effect on macrophage polarization.

Thymoquinone has been shown to alter the Th1/Th2 immune balance leading to predominance of Th1 in allergic disease, as shown in animal models. This substance can suppress IL-4 production in sensitized animal models(Keyhanmanesh et al., 2010).Although it is not clear whether thymoquinone also has the same effect in M. tuberculosis infection, it is expected that thymoquinone could prevent M2 macrophage polarization in tuberculosis.

To study the effect of thymoquinone on lung macrophages and its ability to prevent M2 polarization in M. tuberculosis infection, we used CD68 as a pan-macrophage marker, and CD163 as a marker for M2 phenotype macrophage(Minami et al., 2018; Wang et al., 2020).

Materials and Methods Ethics

The animal experimental study was performed after ethical approval was obtained from Research Ethics Commission of Brawijaya University (Clearance ID: 924-KEP-UB). Experimental procedures were carried out in accordance with the Guide for the Care and Use of Laboratory Animals 8th edition 2011 published by the US National Academy of Sciences.

Animals

We used two months old female Rattus norvegicus rats for this study. The animals were maintained at animal facility of Institute of Tropical Disease Universitas Airlangga, Surabaya. Before starting of the study, two weeks acclimatization was carried out for experimental animals to adapt to the new environment. Rats were fed with standard pellets and water were supplied adequately.

Inoculation

M. tuberculosis strain H37Rv was obtained from Institute of Tropical Disease Universitas Airlangga, Surabaya. The aliquot were contain of 105 cfu/mLM. tuberculosis. To allow inoculation, the rats were anesthetized using intramuscular injection of ketamine-xylazine (1:1) cocktail.Instillation of 0.2 mL aliquot was performed through tracheostomy as previously described(Ribeiro et al., 2015).

Thymoquinone

Thymoquinone (98%) was purchased from Sigma Aldrich Co. (St. Louis, Missouri, USA). This was mixed with DSMO to constitute 10 mg/mL solution. The solution was given throughoral gavage route every morning during study period.

Study design

Rats were divided into five groups, each consisted of 5 rats. The rats in all groups were infected withM. tuberculosis strain H37Rv, except those in negative control group.After 3 weeks, group 1-3 were treated with thymoquinone 25, 50 and 75 mg/kg body weight, respectively. The positive (group 4)and negative (group 5) control groups were treated with DSMO only.

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All rats were ethically killed by intramuscular injection of ketamine-xylazine cocktail at day-21 from the starting of thymoquinone treatment.The lungs were taken and preserved within formalin.

Immunohistochemistry

Tissue preparation, immunohistochemistry staining were conducted at Laboratory of Anatomical Pathology, Brawijaya University. Lung tissues were prepared in paraffin. For immunohistochemical staining, 3-4 micron sections were prepared on the object glasses at a temperature of 60oC for 2 hours. After deparaffination and fixationwith 90 and 80% ethanol solution for 3 minutes each, specimens were rinsed with distilled water and phosphate buffer saline (PBS).To remove endogenous peroxidase, methanol and 3% H2O2were used for 20 minutes.

After antigen retrieval and cooling down, slides were immersed in PBS for three minutes and placed in a moisture chamber.After application of backgroundsniper and 10 minutes incubation, the slides were then dripped with the mouse CD68 Antibody (3F103): sc-70761 (Santa Cruz biotechnology, inc., Dallas, Texas, USA), or mouse CD163 Antibody (ED2): sc-58965 (Santa Cruz biotechnology, inc., Dallas, Texas, USA)and incubated for 1 hour.After washing with distilled water and PBS, the slideswere dripped with polymer and incubated for 30 minutes.

AfterDABchromogenstaining, Mayer's haematoxylinwas used for counterstain. Finally,the slideswere observed using Olympus BX51 dotSlide Digital Virtual Microscopy System (Olympus corp., Shinjuku, Tokyo, Japan) and the images were reviewed using accompanying OlyVIA 2.4 software.

Statistical analysis.

Statistical analyses were performed using Statistic Package of the Social Science software, version 22.0 (SPSS) (IBM, Chicago, US). Data were presented as mean + standard deviation in figures.

One-way analysis of variance test was used to compare mean values between groups, followed by Tukey post hoc test. Kruskal-Wallis test was used when data was not normally nor homogenously distributed, followed by serial Mann-Whitney test. A p-value of <0.05 was considered statistically significant.

Results

Although not statistically significant, three weeks after M. tuberculosis infection, CD68 macrophage expression in rat lung tissue tend to increase. The administration of thymoquinone did not seem to increase CD68 macrophage expression as compared to positive control group.

However, 50 mg/kg BW thymoquinone grouphad highest CD68 macrophage expression (229 + 58.1 cell/hpf), which significantly different compared to negative control (Figure 1).

Figure 1. Lung tissue CD68 macrophage cells of rat infected with M.tuberculosis. CD68 macrophage cells of TQ50 group was significantly higher than negative control group (*p<0.005), but was not significantly different to those of TQ25, TQ75 or positive control group.

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Data are expressed as mean +SD (n=5). hpf: high power field; TQ25, TQ50 and TQ75:

thymoquinone at dose of 25, 50 and 75 mg/kgBW, respectively.

The expression of CD163 macrophage in rat lung tissue was significantly increased three weeks after infection with M. tuberculosis (150 + 73.6 vs 86 + 9.7 cells/hpf). Thymoquinone at dose of 25 mg/kgBW was significantly reduce CD163 macrophage expression (86 + 27.5 cells/hpf) as compared to positive control group. It was also observed that the expression of CD163 macrophage was significantly lower in thymoquinone 25 mg/kgBW group than that of thymoquinone 75 mg/kgBW group (Figure 2).

Figure 2. Lung tissue CD163 macrophage cells of rat infected with M.tuberculosis. CD163 macrophage cells of positive control group was significantly higher than negative control group (*p<0.05). CD163 macrophage cells of TQ25 group was significantly lower than positive control group (**p<0.05), and significantly lower than TQ75 group (#p<0.05).

Data are expressed as mean +SD (n=5). hpf: high power field; TQ25, TQ50 and TQ75:

thymoquinone at dose of 25, 50 and 75 mg/kgBW, respectively. Kruskal-Wallis test was used.

The ratio of CD68 to CD163 macrophage expression of positive control group was not significantly different with negative control group (1.4 + 0.73 vs 1.7 + 0.35)). However, the administration of thymoquinone at dose of 25 and 50 mg/kg BW significantly increased the ratio of CD68 to CD163 macrophage (2.4 + 0.65 and 2.1 + 0.75, respectively) as compared to positive control group (Figure 3).

Figure 3.Lung tissue CD68 to CD163 macrophage ratio of rat infected with M.tuberculosis.The ratiowas significantly different between groups (p=0.009). CD68 to CD163 ratio of TQ25 and TQ50 were significantly higher(*,**p<0.05) compared to positive control group.

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Data are expressed as mean + SD (n=5). TQ25, TQ50 and TQ75: thymoquinone at dose of 25, 50 and 75 mg/kgBW, respectively.

Discussion

Upon various pulmonary insults, such as infection, monocytes rapidly migrates to the site of inflammation and differentiate into tissue macrophage. Depending on the microenvironment,macrophage can later change its phenotype to either M1 pro-inflammatory or M2 anti-inflammatory macrophage; although this classification is not completely precise and various other phenotypes may occur(Rajaram et al., 2014; Robb et al., 2016).Alveolar macrophage which resides in pulmonary alveoli and inter-alveolar septum is the first defense phagocyte to encounter M. tuberculosis(Cooper, 2009). The delay of T cell response initiation is due to M.

tuberculosis ability to dwell in alveolar macrophage and prevent cell apoptosis, which subsequently allow dendritic cell (DC) to present M. tuberculosis antigen to naive T cell CD4 only after 14 days after infection(Cooper, 2009; Srivastava et al., 2014).As disease progresses in active TB, macrophage differentiation is shifted toward M2 macrophages, which are generally anti- inflammatory and poor antigen-presenting cells. Thismacrophage exhibit impaired pathogen-killing ability(Khan et al., 2019; Liu et al., 2017; Wang et al., 2020).

Although there was only slight increase of CD68 macrophages number three weeks after M.

tuberculosis infection in the present study,the significant increased number of CD163 macrophage indicate macrophage phenotype shifting to predominantly M2 macrophage after M. tuberculosis infection. This result demonstrated that virulent strain H37Rv M. tuberculosis has ability to alter lung tissue macrophage micro environment and induce itsdifferentiation toward M2 macrophage(Huang et al., 2015; Khan et al., 2019; Srivastava et al., 2014).

M.tuberculosis has some mechanisms to evade host immune response, shifting macrophage polarization to M2 phenotypeis of most important.Astudy showed that IL-1 receptor associated kinase-M (IRAK-M), a negative regulator of TLR, increased in H37Rv strainM. tuberculosis infected macrophage and its over-expression lead to M2 macrophage polarization(Shen et al., 2017;

Thiriot et al., 2020).Mycobacterial modulins Man-LAM of M.tuberculosis has been known to increaseIrak-M gene expression, which later inhibit IL-12 production from macrophage and suppress its phagocytic ability through attenuation of NF-B(Pathak et al., 2005).

M. tuberculosis, dependent on host type I interferons (IFN) signalling, induces an IFN-related gene expression signature in infected macrophages and reduce the production of IL-1ß(Novikov et al., 2011).TypeI IFN produced by accumulated B cell in lung of M. tuberculosis infected mice favour macrophage polarization to M2. A study showed that upon exposure to supernatant of M.tuberculosis stimulated B cell, macrophage polarized to alternatively activated M2, dependent on type-I IFN(Bénard et al., 2018).

Another study had showed that through stimulation of IL-1ß production of dendritic cell, M.

tuberculosis is able to increase IL-4 cytokine production and shift differentiation of CD4Tcell towards Th2 predominance.This,in turn, may stimulate macrophages differentiation into M2 which has a lower phagocytic ability(Dwivedi et al., 2012).

Thymoquinone is an active agent of Nigella sativa seeds, which has traditionally been used to treat various ailments and has been known to have antioxidative, anti-inflammatory, and immunomodulatory activities(Darakhshan et al., 2015). In addition to its anti-bacterial effect, thymoquinone also has anti-tubercular activity in vitro(Dera et al., 2021; Dey et al., 2014;

Randhawa, 2011).It had also been shown that thymoquinone increase rat peritoneal macrophages IL-12 secretion and phagocytic activity(Akrom and Mustofa, 2017).However, its benefit and

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immunomodulatory effect on M. tuberculosis infection and development of tuberculosis disease has not been studied.

To the best of our knowledge, this study is the first to report in vivoimmunomodulatory effect of thymoquinone on macrophage phenotype changes in M. tuberculosis infection. We demonstrated that thymoquinone at low doses (25 mg/kg BW) can inhibit the increase in CD163 macrophages in rat lung tissue after M. tuberculosis infection. Our study also showed that thymoquinone can increase the ratio of CD68 to CD163 after M. tuberculosis infection. These indicate that thymoquinone has ability to inhibit the differentiation of macrophage into M2 phenotype, thus maintaining pro inflammatory function of macrophage and provide intracellular mycobacterial killing in the lung tissue macrophage.

A study showed that thymoquinone increase the phagocytic activity of rat peritoneal macrophage and IL-12 production(Akrom and Mustofa, 2017). It had also been demonstrated that thymoquinone upregulate macrophage phagocytic activity, respiratory burst and cytokines production, such as IL- 1ß, IL-2, and IL-6; and concomitantly increased IFN-ɣ to IL-4 ratio(Miliani et al., 2018). An in vitro study showed that thymoquinone has ability to suppress IL-5 and IL-13 RNA expression and protein productionof LPS-stimulated mast cells, but do not affect IL-10 production(El Gazzar, 2007). However, another study demonstrated that thymoquinone supress NO production of mouse macrophage cells infected with M. tuberculosis, and inhibited the increase of iNOS, IL-6 and TNF-

 expression of human monocyte THP-1 cell line infected with M.tuberculosis(Mahmud et al., 2017).

The balance of Th1/Th2 plays important role in M1 and M2 macrophage polarization. Through the cellular metabolic alteration involving oxidative phosphorylation and glycolysis, macrophages polarize into M1 in response to IFN-released by infected macrophage as well as Th1 CD4 T-cell;

and into M2 in response to Th2 cytokine such as IL-4 and IL-13(Martinez et al., 2013; O’Neill and Hardie, 2013; Robb et al., 2016).The alteration of macrophage autophagy activity, which play important role in mycobacterium killing in phagolysosome, may also be cellular mechanism affected by these Th1 and Th2 cytokines balance. Macrophage autophagy is induced by IFN-, dependent on irgm1. Contrariwise, through activation of Akt pathway, autophagy is inhibited by IL- 4 and IL-13stimulation to mammalian target of rapamycin (mTOR). In addition, IL-4 and IL-13 inhibit IFN- induced autophagy via the stimulation of STAT6(Harris et al., 2009).Interestingly, a study had demonstratedthat Nigella sativa extract or its active compound, i.e.

thymoquinone,suppresses Th2 cytokine IL-4 in ovalbumin sensitized guinea pigs(Boskabady et al., 2011; Keyhanmanesh et al., 2010).However, there has not been any study reporting the effect of thymoquinone on these inflammatory signatures in M. tuberculosis infection.

IL-1ß secreted by M. tuberculosis infected DC stimulates IL-4 production and induce Th2 differentiation of CD4 T cell(Dwivedi et al., 2012).An in vitro study had demonstrated thatthymoquinone reduced the secretion of IL-4 and increase IFN/IL-4 ratio in stimulated splenocyte(Gholamnezhad et al., 2015).Another study showed that thymoquinone inhibit LPS- induced differentiation and maturation, as well as cytokine release of DC cultured from mice bone marrow(Xuan et al., 2010). Hence, it is possible that thymoquinone inhibit IL-1ß production of DC, thus prevent IL-4 production and CD4 Tcell differentiation into Th2 in M. tuberculosis infection.

However, it requires further investigation to study the effectof thymoquinone on these cytokines in M. tuberculosis infection.

Thymoquinone may decrease M2 macrophage through suppression to type IIFNwhich block responsiveness of macrophage to IFN-. Type I IFNhas been known to blockM. tuberculosis infected macrophage responsiveness to IFN-for bacterial killing, as well as for IL-12 production(McNab et al., 2015; McNab et al., 2014).Moreover, it has been known to inhibit production of protective cytokines such as TNF-and IL-1,while increase production of immunosuppressive cytokine IL-10(McNab et al., 2014).A study showed that thymoquinone

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suppresses IRF-3 mediated expression of type I IFNthrough suppression of autophosphorylation of TANK-binding kinase-1 (TBK-1)(Aziz et al., 2018).Thymoquinone suppression to type I interferons expectedly can increase the protective cytokines and decrease of IL-10.

There have been no study whether thymoquinone inhibit M2 macrophage polarization by suppressing IRAK-M. However, a study in LPSactivated macrophage revealed that thymoquinone directly suppress IRAK-1 and its downstream NF-B and AP-1 activity(Hossen et al., 2017).

The limitation of this study is that the changes of macrophage polarization before observation at three weeks since administration of thymoquinone were not known. The inhibition of macrophages polarization shift to the M2 phenotype in thymoquinone treatment group could have occured before the observation at the third week.

In conclusion, thymoquinone can inhibit M2 polarization of lung macrophage in rat infected with M. tuberculosis. This effect may be due to intracellular target of thymoquinone or its ability to change macrophage micro environment. Further investigations are required to study the mechanisms of thymoquinone on affecting macrophage phenotype shifting in M. tuberculosis infection.

Acknowledgment

The authors would like to thank dr. Kenti Wantri Anita and dr. Aina Angelina (Department of Pathological Anatomy, Faculty of Medicine, Universitas Brawijaya).

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