S100A8/A9 Proteins Mediate Neutrophilic Inflammation and Lung Pathology during Tuberculosis

Abstract

Rationale: A hallmark of pulmonary tuberculosis (TB) is the formation of granulomas. However, the immune factors that drive the formation of a protective granuloma during latent TB, and the factors that drive the formation of inflammatory granulomas during active TB, are not well defined. Objectives: The objective of this study was to identify the underlying immune mechanisms involved in formation of inflammatory granulomas seen during active TB. Methods: The immune mediators involved in inflammatory granuloma formation during TB were assessed using human samples and experimental models of Mycobacterium tuberculosis infection, using molecular and immunologic techniques. Measurements and Main Results: We demonstrate that in human patients with active TB and in nonhuman primate models of M. tuberculosis infection, neutrophils producing S100 proteins are dominant within the inflammatory lung granulomas seen during active TB. Using the mouse model of TB, we demonstrate that the exacerbated lung inflammation seen as a result of neutrophilic accumulation is dependent on S100A8/A9 proteins. S100A8/A9 proteins promote neutrophil accumulation by inducing production of proinflammatory chemokines and cytokines, and influencing leukocyte trafficking. Importantly, serum levels of S100A8/ A9 proteins along with neutrophil-associated chemokines, such as keratinocyte chemoattractant, can be used as potential surrogate biomarkers to assess lung inflammation and disease severity in human TB. Conclusions: Our results thus show a major pathologic role for S100A8/A9 proteins in mediating neutrophil accumulation and inflammation associated with TB. Thus, targeting specific molecules, such as S100A8/A9 proteins, has the potential to decrease lung tissue damage without impacting protective immunity against TB.Keywords: inflammation; tuberculosis; neutrophil; S100A8/A9 proteins; granuloma A hallmark of pulmonary tuberculosis (TB) in humans and experimentally infected animals is the formation of granulomas. However, the immune factors that drive the formation of the protective granuloma during latent TB, and the factors that drive the inflammatory granulomas formed during active TB, are not well defined. What This Study Adds to the FieldThis study demonstrates the dominant presence of neutrophils producing S100 proteins within the inflammatory lung granulomas of patients with active TB. This study also describes a link between S100A8/A9 protein induction, neutrophil accumulation, and pathology associated with the inflammatory granuloma formed during TB, because S100A8/A9 deficiency in mice reverses exacerbated inflammation during TB. In addition, this study demonstrates the potential use of S100A8/A9 proteins along with neutrophilattracting chemokines in serum as surrogate biomarkers to assess inflammation and disease severity in TB in humans.

CD4 + T-cell–independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

“…We have previously demonstrated that the presence of inducible lymphoid follicles, also termed inducible BALT (iBALT), correlates with protection from TB (33). Animals with LTBI harbor greater areas of iBALT within lung lesions relative to animals with ATB, in which BALT was replaced by neutrophils (34). In our current study, nonreactivators often formed multiple, well-organized areas of lymphoid follicles, as observed by H&E staining, as well as by chromogenic staining against CD20 (Fig.…”

“…Previously, we have shown that increased BALT presence was associated with increased protection in mice, NHPs, and humans (33,34). More importantly, protective immunity to TB, induced by a novel vaccine, also correlated strongly with the presence of BALT (14).…”

Helminth-induced arginase-1 exacerbates lung inflammation and disease severity in tuberculosis

“…We show that an outcome of S. mansoni infection and the induction of type 2 granulomas within the Mtb-infected lung is the reduced formation of lymphoid follicle-containing granulomas in helminth/Mtb-coinfected hosts and increased accumulation of inflammatory granulocytes. In addition, using Mtb-infected genetically diverse mice, which exhibit heterogeneity in inflammation and disease severity (14), we demonstrate that exacerbated lung inflammation -even in the absence of helminth coinfection -is associated with increased arginase-1 activity. Importantly, increased arginase-1 activity in the serum of patients with ATB is associated with exacerbated lung inflammatory damage and disease severity.…”

“…Our recent studies have demonstrated that, in TB, protective granulomas contain distinct B cell lymphoid follicles harboring T cells and macrophages, while inflammatory granulomas lack well-formed B cell-containing lymphoid follicles and instead contain neutrophils that mediate inflammation (13,14). Thus, we next measured the area occupied by lymphoid B cell follicles and found that S. mansoni coinfection in Mtb-infected mice resulted in decreased and poorly formed B cell follicles ( Figure 2C).…”

“…These inflammatory effects are mediated by macrophages expressing arginase-1 and can be reversed by treatment with antihelminthics. Our recent work has put forth the new paradigm that protective outcomes in TB are associated with formation of lymphoid follicles within the tubercle granuloma (13), while increased disease severity is associated with accumulation of neutrophils and exacerbated inflammation (14). We show that an outcome of S. mansoni infection and the induction of type 2 granulomas within the Mtb-infected lung is the reduced formation of lymphoid follicle-containing granulomas in helminth/Mtb-coinfected hosts and increased accumulation of inflammatory granulocytes.…”