Infectious disease, the innate immune response, and fibrosis - PubMed (original) (raw)

Review

Infectious disease, the innate immune response, and fibrosis

Alessia Meneghin et al. J Clin Invest. 2007 Mar.

Abstract

The unrelenting and destructive progression of most fibrotic responses in the pulmonary, cardiovascular, integumentary, and alimentary systems remains a major medical challenge for which therapies are desperately needed. The pathophysiology of fibrosis remains an enigma, but considerable research and debate surrounds the question of whether chronic inflammation is the key driver of unrestrained wound healing (i.e., the fibrotic response) in these and other organ systems. This Review describes how infectious pathogens, chronic inflammation, and unrestrained fibroproliferation are likely to be part of a dynamic, unrelenting process propelling human fibrotic diseases.

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Figures

Figure 1

Figure 1. Persistent infectious stimuli initiate and sustain the fibrotic process.

Pathogens such as bacteria, viruses, fungi, and multicellular parasites represent major tissue injurious signals. The host response, mediated by the innate immune system, is intricately directed toward recognizing PAMPs through a myriad of PRRs. The concerted inflammatory and immune efforts of several immune and nonimmune cell types, including (but not limited to) classically activated macrophages (M1 macrophages), T cells, eosinophils, B cells, DCs, neutrophils, epithelial cells, and fibroblasts, contribute to the chronic inflammatory response. A dominant Th1 cytokine response normally characterizes an effective immune response against most pathogens, except most multicellular and extracellular parasites. Should pathogens and their byproducts be effectively cleared, the affected tissue often heals appropriately and the inflammatory process resolves. However, pathogens use various survival strategies to avoid elimination, and this leads to their persistence or the persistence of their byproducts in the host. The cytokine pattern associated with the ineffective response is often skewed toward the Th2 cytokine pattern. The resulting fibrotic response might be a consequence of the actions of unique cells such as the ECM component–synthesizing myofibroblast and the alternatively activated macrophage (M2 macrophage). The fibrotic response, in turn, might facilitate the persistence of pathogens and their byproducts, thereby allowing this vicious cycle to continue.

Figure 2

Figure 2. A defective host response facilitates chronic pulmonary fibrosis.

Similar to other organ systems directly exposed to the external environment, the lung confronts infectious agents on a continual basis. Should transcript and protein components of these infectious pathogens persist, the immune response appears to skew to a Th2 cytokine profile (i.e., increased IL-4 and IL-13). Secondary or repetitive exposure to infectious agents in this immunoregulated environment might then exacerbate the fibrotic response due the lack of an effective Th1 immune response. This scenario can be observed in the context of a secondary viral insult in the form of a herpesvirus. Experimentally, MHV-68 markedly enhanced fibrosis in a Th1-deficient environment (73). Current data suggests that MHV-68 exacerbates the tissue fibrotic response in mice by contributing gene products that can neutralize necessary innate immune cytokines (through cytokine-binding proteins such as M3) or induce rapid cell proliferation (through the viral chemokine receptor vGPCR) (our unpublished observations). Therefore, the fibrotic response might be exacerbated by secondary and repeated pathogen insults. Viral byproducts might be particularly important in perpetuating fibrosis.

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