Selective M1 macrophage polarization in granuloma-positive and granuloma-negative Crohn’s disease, in comparison to intestinal tuberculosis

다국어 초록 (Multilingual Abstract)

Background/Aims: Classical M1 macrophage activation exhibits an inflammatory phenotype while alternative M2 macrophage activation exhibits an anti-inflammatory phenotype. We aimed to determine whether there are discriminant patterns of macrophage polarization in Crohn’s disease (CD) and intestinal tuberculosis (iTB). Methods: Colonic mucosal biopsies from 29 patients with iTB, 50 with CD, and 19 controls were examined. Dual colored immunohistochemistry was performed for iNOS/CD68 (an M1ϕ marker) and CD163/CD68 (an M2ϕ marker), and the ratio of M1ϕ to M2ϕ was assessed. To establish the innate nature of macrophage polarization, we analyzed the extent of mitochondrial depolarization, a key marker of inflammatory responses, in monocyte-derived macrophages obtained from CD and iTB patients, following interferon-γ treatment.
Results: M1ϕ polarization was more prominent in CD biopsies (P=0.002) than in iTB (P=0.2) and control biopsies. In granuloma-positive biopsies, including those in CD, M1ϕ predominance was significant (P=0.001). In iTB, the densities of M1ϕ did not differ between granuloma-positive and granuloma-negative biopsies (P=0.1). Interestingly, higher M1ϕ polarization in CD biopsies correlated with high inflammatory response exhibited by peripheral blood-derived monocytes from these patients.
Conclusions: Proinflammatory M1ϕ polarization was more common in colonic mucosa of CD patients, especially in the presence of mucosal granulomas. Further characterization of the innate immune system could help in clarifying the pathology of iTB and CD.

참고문헌 (Reference)

1 Schaale K, "Wnt6 is expressed in granulomatous lesions of Mycobacterium tuberculosis-infected mice and is involved in macrophage differentiation and proliferation" 191 : 5182-5195, 2013

2 Kamada N, "Unique CD14 intestinal macrophages contribute to the pathogenesis of Crohn disease via IL-23/IFN-gamma axis" 118 : 2269-2280, 2008

3 Hansen G, "The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation" 134 : 496-507, 2008

4 Neurath MF, "The role of Th1/Th2 polarization in mucosal immunity" 8 : 567-573, 2002

5 Mantovani A, "The chemokine system in diverse forms of macrophage activation and polarization" 25 : 677-686, 2004

6 Martinez FO, "The M1 and M2 paradigm of macrophage activation: time for reassessment" 6 : 13-, 2014

7 Qualls JE, "Suppression of experimental colitis by intestinal mononuclear phagocytes" 80 : 802-815, 2006

8 Turner K, "Significance of the epithelioid granuloma in biopsies of Crohn's colitis" 20 : 2271-2275, 2014

9 Maloy KJ, "Regulatory T cells in the control of immune pathology" 2 : 816-822, 2001

10 Buechler C, "Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli" 67 : 97-103, 2000

11 Jablonski KA, "Novel markers to delineate murine M1 and M2 macrophages" 10 : e0145342-, 2015

12 Tobal K, "Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia" 4 : 486-489, 1990

13 Lissner D, "Monocyte and M1 macrophage-induced barrier defect contributes to chronic intestinal inflammation in IBD" 21 : 1297-1305, 2015

14 Lugo-Villarino G, "Macrophage polarization: convergence point targeted by mycobacterium tuberculosis and HIV" 2 : 43-, 2011

15 Barros MH, "Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages" 8 : e80908-, 2013

16 Magnusson MK, "Macrophage and dendritic cell subsets in IBD: ALDH+ cells are reduced in colon tissue of patients with ulcerative colitis regardless of inflammation" 9 : 171-182, 2016

17 Mills CD, "M-1/M-2 macrophages and the Th1/Th2 paradigm" 164 : 6166-6173, 2000

18 Doyle AG, "Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-gamma" 24 : 1441-1445, 1994

19 Stein M, "Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation" 176 : 287-292, 1992

20 Ahuja V, "Inflammatory bowel disease: the Indian augury" 31 : 294-296, 2012

21 Ogino T, "Increased Th17-inducing activity of CD14+ CD163 low myeloid cells in intestinal lamina propria of patients with Crohn's disease" 145 : 1380-1391, 2013

22 Matta SK, "Hypoxia and classical activation limits Mycobacterium tuberculosis survival by Akt-dependent glycolytic shift in macrophages" 2 : 16022-, 2016

23 Sulahian TH, "Human monocytes express CD163, which is upregulated by IL-10 and identical to p155" 12 : 1312-1321, 2000

24 Koboziev I, "Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation" 1207 (1207): E86-E93, 2010

25 Freeman HJ, "Granuloma-positive Crohn's disease" 21 : 583-587, 2007

26 Stange EF, "European evidence based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis" 55 (55): i1-i15, 2006

27 Pratap Mouli V, "Endoscopic and clinical responses to anti-tubercular therapy can differentiate intestinal tuberculosis from Crohn's disease" 45 : 27-36, 2017

28 Kuhl AA, "Diversity of intestinal macrophages in inflammatory bowel diseases" 6 : 613-, 2015

29 de Jong YP, "Development of chronic colitis is dependent on the cytokine MIF" 2 : 1061-1066, 2001

30 Moser M, "Dendritic cell regulation of TH1-TH2 development" 1 : 199-205, 2000

31 Lacey DC, "Defining GM-CSFand macrophage-CSF-dependent macrophage responses by in vitro models" 188 : 5752-5765, 2012

32 Isidro RA, "Colonic macrophage polarization in homeostasis, inflammation, and cancer" 311 : G59-G73, 2016

33 Makharia GK, "Clinical, endoscopic, and histological differentiations between Crohn's disease and intestinal tuberculosis" 105 : 642-651, 2010

34 Mackaness GB, "Cellular resistance to infection" 116 : 381-406, 1962

35 Tamoutounour S, "CD64 distinguishes macrophages from dendritic cells in the gut and reveals the Th1-inducing role of mesenteric lymph node macrophages during colitis" 42 : 3150-3166, 2012

36 Thiesen S, "CD14(hi) HLA-DR(dim) macrophages, with a resemblance to classical blood monocytes, dominate inflamed mucosa in Crohn's disease" 95 : 531-541, 2014

37 Paustian F, "Bockus gastroenterology" Saunders 3304-, 1995

38 Blumberg RS, "Animal models of mucosal inflammation and their relation to human inflammatory bowel disease" 11 : 648-656, 1999

39 Cossarizza A, "A new method for the cytofluorimetric analysis of mitochondrial membrane potential using the J-aggregate forming lipophilic cation 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine iodide (JC-1)" 197 : 40-45, 1993