The IL-17F/IL-17RC Axis Promotes Respiratory Allergy in the Proximal Airways

Summary The interleukin 17 (IL-17) cytokine and receptor family is central to antimicrobial resistance and inflammation in the lung. Mice lacking IL-17A, IL-17F, or the IL-17RA subunit were compared with wild-type mice for susceptibility to airway inflammation in models of infection and allergy. Signaling through IL-17RA was required for efficient microbial clearance and prevention of allergy; in the absence of IL-17RA, signaling through IL-17RC on epithelial cells, predominantly by IL-17F, significantly exacerbated lower airway Aspergillus or Pseudomonas infection and allergic airway inflammation. In contrast, following infection with the upper respiratory pathogen Staphylococcus aureus , the IL-17F/IL-17RC axis mediated protection. Thus, IL-17A and IL-17F exert distinct biological effects during pulmonary infection; the IL-17F/IL-17RC signaling axis has the potential to significantly worsen pathogen-associated inflammation of the lower respiratory tract in particular, and should be investigated further as a therapeutic target for treating pathological inflammation in the lung

Noncanonical Fungal Autophagy Inhibits Inflammation in Response to IFN-γ via DAPK1

Defects in a form of noncanonical autophagy, known as LC3-associated phagocytosis (LAP), lead to increased inflammatory pathology during fungal infection. Although LAP contributes to fungal degradation, the molecular mechanisms underlying LAP-mediated modulation of inflammation are unknown. We describe a mechanism by which inflammation is regulated during LAP through the death-associated protein kinase 1 (DAPK1). The ATF6/C/EBP-β/DAPK1 axis activated by IFN-γ not only mediates LAP to Aspergillus fumigatus but also concomitantly inhibits Nod-like receptor protein 3 (NLRP3) activation and restrains pathogenic inflammation. In mouse models and patient samples of chronic granulomatous disease, which exhibit defective autophagy and increased inflammasome activity, IFN-γ restores reduced DAPK1 activity and dampens fungal growth. Additionally, in a cohort of hematopoietic stem cell-transplanted patients, a genetic DAPK1 deficiency is associated with increased inflammation and heightened aspergillosis susceptibility. Thus, DAPK1 is a potential drugable player in regulating the inflammatory response during fungal clearance initiated by IFN-γ

IL-1 receptor antagonist ameliorates inflammasome-dependent inflammation in murine and human cystic fibrosis

Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF

Thymosin β4 promotes autophagy and repair via HIF-1α stabilization in chronic granulomatous disease

Chronic granulomatous disease (CGD) is a genetic disorder of the NADPH oxidase characterized by increased susceptibility to infections and hyperinflammation associated with defective autophagy and increased inflammasome activation. Herein, we demonstrate that thymosin beta 4 (T beta 4), a g-actin sequestering peptide with multiple and diverse intracellular and extracellular activities affecting inflammation, wound healing, fibrosis, and tissue regeneration, promoted in human and murine cells noncanonical autophagy, a form of autophagy associated with phagocytosis and limited inflammation via the death-associated protein kinase 1. We further show that the hypoxia inducible factor-1 (HIF-1)alpha was underexpressed in CGD but normalized by T beta 4 to promote autophagy and up-regulate genes involved in mucosal barrier protection. Accordingly, inflammation and granuloma formation were impaired and survival increased in CGD mice with colitis or aspergillosis upon T beta 4 treatment or HIF-1 alpha stabilization. Thus, the promotion of endogenous pathways of inflammation resolution through HIF-1 alpha stabilization is druggable in CGD by T beta 4

Anakinra Activates Superoxide Dismutase 2 to Mitigate Inflammasome Activity

Contains fulltext : 234973.pdf (Publisher’s version ) (Open Access

COVID-19 and beyond: Reassessing the role of thymosin alpha1 in lung infections

The recent COVID-19 pandemic has catalyzed the attention of the scientific community to the long-standing issue of lower respiratory tract infections. The myriad of airborne bacterial, viral and fungal agents to which humans are constantly exposed represents a constant threat to susceptible individuals and bears the potential to reach a catastrophic scale when the ease of inter-individual transmission couples with a severe pathogenicity. While we might be past the threat of COVID-19, the risk of future outbreaks of respiratory infections is tangible and argues for a comprehensive assessment of the pathogenic mechanisms shared by airborne pathogens. On this regard, it is clear that the immune system play a major role in dictating the clinical course of the infection. A balanced immune response is required not only to disarm the pathogens, but also to prevent collateral tissue damage, thus moving at the interface between resistance to infection and tolerance. Thymosin alpha1 (Tα1), an endogenous thymic peptide, is increasingly being recognized for its ability to work as an immunoregulatory molecule able to balance a derailed immune response, working as immune stimulatory or immune suppressive in a context-dependent manner. In this review, we will take advantage from the recent work on the COVID-19 pandemic to reassess the role of Tα1 as a potential therapeutic molecule in lung infections caused by either defective or exaggerated immune responses. The elucidation of the immune regulatory mechanisms of Tα1 might open a new window of opportunity for the clinical translation of this enigmatic molecule and a potential new weapon in our arsenal against lung infections

Pathogenic NLRP3 Inflammasome Activity during Candida Infection Is Negatively Regulated by IL-22 via Activation of NLRC4 and IL-1Ra

Item does not contain fulltextCandida albicans is a well-tolerated resident of human mucosal tissues. This implies that host defense mechanisms cooperate to limit inflammation while controlling fungal burden. The cytokine IL-22 and inflammasomes are essential components of the mucosal responses to C. albicans. How these components cooperate to mediate the balance of inflammation and host defense is not explored. We find that NLRP3 inflammasome activation promotes neutrophil recruitment and inflammation during infection and that this activity is counteracted by IL-22. Mechanistically, IL-22 activated NLRC4 for sustained production of the IL-1 receptor antagonist IL-1Ra, which restrained NLRP3 activity. Symptomatic infection in mice and humans occurred under conditions of IL-1Ra deficiency and was rescued in mice by replacement therapy with the recombinant IL-1Ra anakinra. Thus, pathogenic inflammasome activity during Candida infection is negatively regulated by the IL-22/NLRC4/IL-1Ra axis. Our findings offer insights into the pathogenesis of C. albicans and suggest therapeutic avenues for candidiasis