مقاله انگلیسی رایگان در مورد تنظیم منفی اینتگرین CD11b سیگنال Mincle توسط مجموعه Lyn–SIRPα–SHP1

The hallmark of Mycobacterium tuberculosis (Mtb) infection is the formation of a granuloma, a compact aggregate of immune cells.1 The granuloma has been thought to function as a host defense mechanism to prevent further spread of Mtb; however, recent studies suggest that the granuloma can also shelter the bacteria and ensure persistence of these organisms in a latent form.2,3 Therefore, clearance of the mycobacteria that persist in the granuloma is required for efficient clearance of the infection. Granuloma formation is initiated by an orchestrated production of cytokines and chemokines coupled with the upregulation of selectins and integrins on immune cells to recruit and activate different populations of leukocytes.4 As granuloma formation progresses, the intense proinflammatory responses are suppressed by negative modulators, to prevent excessive granuloma formation.5 The most prominent antiinflammatory cytokine involved in the downregulation of granuloma formation is interleukin (IL)-10, which antagonizes the activity of IL-17 and interferon (IFN)-γ, thereby lessening the protective immune responses of macrophages.6,7 Additionally, IL-10 may inhibit antigen presentation by dendritic cells (DCs) via blockade of major histocompatibility complex molecules.8 This compromised immune environment may, therefore, enable the bacteria to evade host immune surveillance and survive for a long time in the lungs, ultimately leading to a chronic infection. Hence, understanding the protective mechanism of negative regulators of granuloma formation will elucidate key targets for the development of immune therapies to fight Mtb infection. Mtb carries diverse pathogen-associated molecular patterns (PAMPs) that can initiate an inflammatory response in the host. Among these PAMPs, the virulent cord factor trehalose6,6-dimycolate (TDM) is specifically recognized by macrophage-inducible C-type lectin (Mincle), and this cord factor alone leads to a granulomatous response through the robust production of nitric oxide (NO) and various proinflammatory cytokines and chemokines, including IL-6, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1.9–11 Additionally, TDM stimulation critically enhances the cellular adhesion of neutrophils by increasing their surface expression of integrin CD11b/CD18.12 Amplified integrin surface expression allows neutrophils to infiltrate into and accumulate around infected sites, enabling recruitment of additional neutrophils to kill the bacteria. Thus Mincle appears to have a key role in the fight of leukocytes against mycobacteria infection. Although the activation of the proinflammatory response by Mincle has been studied extensively, the negative mediators that specifically restrain Mincle signaling during granuloma formation remain to be elucidated.