Peripheral cells from patients with systemic sclerosis disease co-expressing M1 and M2 monocyte/macrophage surface markers: Relation to the degree of skin involvement.

The monocyte/macrophage lineage cells were found involved in the pathogenesis of systemic sclerosis (SSc) disease. The naïve macrophages are activated either to M1 cells with proinflammatory roles or to M2 cells that function to resolve inflammation with tissue repair. Recently, cells with dual phenotypes were detected in SSc disease. So, we aimed in this study to demonstrate different monocyte/macrophage phenotypes in peripheral cells from a group of Egyptian SSc patients, correlating percentages of these cells with the clinical findings in patients. The study participants comprised 41 patients with diffuse cutaneous SSc disease and 25 healthy individuals as controls. Clinical, radiological, and laboratory tests were conducted for SSc patients. Different phenotypes of the monocyte/macrophage subsets were identified in peripheral blood of patients and controls by flow cytometry for characteristic M1 (CD80, CD86, and TLR4) and M2 (CD204, CD163 and CD206) markers. SSc patients showed higher percentages of peripheral cells of the M1, M2, and mixed M1/M2 phenotypes within the monocyte/macrophage lineage compared to controls. Different cell phenotypes were associated significantly with the disease duration, modified Rodnan's score, the Medsger skin score, and the Medsger lung in SSc patients. Some cells with the M1/M2 phenotypes were higher in SSc patients with pitting scars, arthritis, and myalgia.

Mohamed ME ，Gamal RM ，El-Mokhtar MA ，Hassan AT ，Abozaid HSM ，Ghandour AM ，Abdelmoez A Ismail S ，A Yousef H ，H El-Hakeim E ，S Makarem Y ，Abdellatif Awad A ... -  《-》

A circulating cell population showing both M1 and M2 monocyte/macrophage surface markers characterizes systemic sclerosis patients with lung involvement.

Trombetta AC ，Soldano S ，Contini P ，Tomatis V ，Ruaro B ，Paolino S ，Brizzolara R ，Montagna P ，Sulli A ，Pizzorni C ，Smith V ，Cutolo M ... -  《RESPIRATORY RESEARCH》

Characterization of monocyte/macrophage subsets in the skin and peripheral blood derived from patients with systemic sclerosis.

Higashi-Kuwata N ，Jinnin M ，Makino T ，Fukushima S ，Inoue Y ，Muchemwa FC ，Yonemura Y ，Komohara Y ，Takeya M ，Mitsuya H ，Ihn H ... -  《-》

Polarization of Human Monocyte-Derived Cells With Vitamin D Promotes Control of Mycobacterium tuberculosis Infection.

Background: Understanding macrophage behavior is key to decipher Mycobacterium tuberculosis (Mtb) pathogenesis. We studied the phenotype and ability of human monocyte-derived cells polarized with active vitamin D [1,25(OH)2D3] to control intracellular Mtb infection compared with polarization of conventional subsets, classical M1 or alternative M2. Methods: Human blood-derived monocytes were treated with active vitamin D or different cytokines to obtain 1,25(OH)2D3-polarized as well as M1- and M2-like cells or fully polarized M1 and M2 subsets. We used an in vitro macrophage Mtb infection model to assess both phenotype and functional markers i.e., inhibitory and scavenger receptors, costimulatory molecules, cytokines, chemokines, and effector molecules using flow cytometry and quantitative mRNA analysis. Intracellular uptake of bacilli and Mtb growth was monitored using flow cytometry and colony forming units. Results: Uninfected M1 subsets typically expressed higher levels of CCR7, TLR2, and CD86, while M2 subsets expressed higher CD163, CD200R, and CD206. Most of the investigated markers were up-regulated in all subsets after Mtb infection, generating a mixed M1/M2 phenotype, while the expression of CD206, HLADR, and CD80 was specifically up-regulated (P < 0.05) on 1,25(OH)2D3-polarized macrophages. Consistent with the pro-inflammatory features of M1 cells, Mtb uptake and intracellular Mtb growth was significantly (P < 0.01-0.001 and P < 0.05-0.01) lower in the M1 (19.3%) compared with the M2 (82.7%) subsets 4 h post-infection. However, infectivity rapidly and gradually increased in M1 cells at 24-72 h. 1,25(OH)2D3-polarized monocyte-derived cells was the most potent subset to inhibit Mtb growth at both 4 and 72 h (P < 0.05-0.01) post-Mtb infection. This ability was associated with high mRNA levels of pro-inflammatory cytokines and the antimicrobial peptide LL-37 but also anti-inflammatory IL-10, while expression of the immunosuppressive enzyme IDO (indoleamine 2,3-dioxygenase) remained low in Mtb-infected 1,25(OH)2D3-polarized cells compared with the other subsets. Conclusions: Mtb infection promoted a mixed M1/M2 macrophage activation, and 1,25(OH)2D3-polarized monocyte-derived cells expressing LL-37 but not IDO, were most effective to control intracellular Mtb growth. Macrophage polarization in the presence of vitamin D may provide the capacity to mount an antimicrobial response against Mtb and simultaneously prevent expression of inhibitory molecules that could accelerate local immunosuppression in the microenvironment of infected tissue.

Rao Muvva J ，Parasa VR ，Lerm M ，Svensson M ，Brighenti S ... -  《Frontiers in Immunology》

Downregulated IRF8 in Monocytes and Macrophages of Patients with Systemic Sclerosis May Aggravate the Fibrotic Phenotype.

Monocytes and macrophages may be involved in the pathogenesis of systemic sclerosis (SSc); however, the etiology and regulation of monocyte and macrophage function in SSc remain unknown. IRF8 is a transcriptional regulator that is essential for the differentiation and function of monocytes and macrophages and thus may be involved in the regulation of macrophage phenotypes in SSc fibrosis. In this study, we measured IRF8 levels in circulating monocytes of 26 patients with SSc (diffuse cutaneous SSc, n = 11; limited cutaneous SSc, n = 15) and 14 healthy controls. IRF8 levels were significantly suppressed in monocytes of patients with diffuse cutaneous SSc and correlated negatively with the modified Rodnan total skin thickness score. Next, we assessed expression levels of cell surface markers, cytokine profiles, and components of extracellular matrix in IRF8-silenced monocyte-derived macrophages. IRF8-silenced monocyte-derived macrophages displayed an M2 phenotype and significantly upregulated mRNA and protein levels of profibrotic factors and extracellular matrix components. Finally, we assessed skin fibrosis in myeloid cell-specific IRF8 conditional knockout (Irf8flox/flox; Lyz2Cre/+) mice and found upregulated mRNA levels of extracellular matrix components and increased bleomycin-induced skin fibrosis. In conclusion, altered IRF8 regulation in monocytes and macrophages may be involved in SSc pathogenesis.

Ototake Y ，Yamaguchi Y ，Asami M ，Komitsu N ，Akita A ，Watanabe T ，Kanaoka M ，Kurotaki D ，Tamura T ，Aihara M ... -  《-》