Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease

Abstract

To understand the pathogenesis of chronic inflammatory disease, we analyzed an experimental mouse model of a chronic lung disease that resembles asthma and chronic obstructive pulmonary disease (COPD) in humans. In this model, chronic lung disease develops after infection with a common type of respiratory virus is cleared to trace levels of noninfectious virus. Unexpectedly, the chronic inflammatory disease arises independently of an adaptive immune response and is driven by IL-13 produced by macrophages stimulated by CD1d-dependent TCR-invariant NKT cells. This innate immune axis is also activated in the lungs of humans with chronic airway disease due to asthma or COPD. These findings provide new insight into the pathogenesis of chronic inflammatory disease with the discovery that the transition from respiratory viral infection into chronic lung disease requires persistent activation of a novel NKT cell-macrophage innate immune axis. It has been widely speculated that infections are linked to the development of chronic inflammatory diseases. Although the connection between infection and chronic disease is uncertain, it likely depends on an aberrant immune response. In particular, it is believed that the innate immune system mediates the acute response to an infectious agent 1 , while an atypical adaptive immune response may cause chronic inflammation 2. Furthermore, infectioninduced alterations in the adaptive immune response that produce T cell or antibody-mediated

IL13 activates autophagy to regulate secretion in airway epithelial cells

“…27 Airway goblet cell formation can be efficiently induced by airway delivery of IL33, which leads to macrophage and lymphocyte production of IL13. 14,[30][31][32][33] To test if autophagy plays a role in cytokine-induced inflammation in vivo, we compared the response of wild-type (WT) and Atg16l1 hypomorphic (HM) mice (Atg16l1 HM/HM ) 27 following intranasal administration of IL33. Airways of control mice (na€ ıve vehicle treated) contained few if any detectable goblet cells.…”

From phagocyte diversity and activation to probiotics: Back to Metchnikoff

“…In vivo counterparts of M2 macrophage polarization have been observed in tissue remodelling during ontogenesis [28], chronic inflammation [29][30][31][32][33][34][35][36][37][38][39][40][41][42], cancer [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of immunopathology [35][36][37][38][39][40][41][50][51][52].…”

“…The issue of lineage of the actual effectors of MDSC-mediated suppression is even more relevant when their recruitment and activation in non-lymphoid tissues is considered. For instance, do MDSC retain an immature phenotype in tumour tissues or do they differentiate into tumourassociated macrophages [9][10][11] [9,12,16,17], bacterial [43][44][45][46][47][48][49] and parasitic [50][51][52][53] infections. Evidence has also accumulated that polarized macrophages are more than mere spectators of immunopathology [35][36][37][38][39][40][41][50][51][52].…”

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

“…[27][28][29][30][31][32] However, they can also contribute to the immunopathogenesis of viral diseases. For example, using an experimental mouse model of chronic lung disease triggered by infection with Sendai virus, Kim et al 33 demonstrated that IL-13 production by iNKT cells contributes to pulmonary disease. More recently, Stout-Delgado et al 34 demonstrated that IL-17 production by iNKT cells from aged mice infected with herpes simplex virus 2 is sufficient to promote liver damage and death.…”

“…20,24 -26 For example, during infection with influenza A virus, herpes simplex virus types 1 and 2, and lymphocytic choriomeningitis virus, iNKT cells have a positive role in anti-viral immune responses and virus-associated disease, [27][28][29][30][31][32] whereas during infection with Sendai virus and herpes simplex virus type 2 (only in aged mice), iNKT cells are rather deleterious. 33,34 However, iNKT cells do not seem to participate in anti-viral immunity or control of viral replication during infection with encephalomyocarditis virus and murine cytomegalovirus. [35][36][37] The potential role of iNKT cells in experimental viral infections has also been studied using CD1d-deficient mice, which lack both iNKT cells and vNKT cells.…”