Pneumonia is frequently associated with sepsis, a leading cause of morbidity and mortality worldwide, which is characterized by a non-resolving hyperinflammation. However, specific host components of the pulmonary milieu that regulate the intricate balance between perpetuation of inflammation and restoration of tissue homeostasis are not clearly understood. The complex process of resolution of inflammation is characterized by molecular and cellular events that orchestrate the removal of neutrophils by a process called efferocytosis. This process not only promotes anti-inflammatory and tissue-reparative response, but also negatively regulates granulopoiesis, all contributing to eventually regain a state of homeostasis. An understanding of these events is critical for developing effective prevention and/or treatment strategies for inflammatory immune disorders, including but not limited to sepsis. The long term goal of the proposed research is to characterize pulmonary innate immune components functioning in resolution of inflammation by using a pulmonary pathogen Klebsiella pneumoniae (KPn) which causes severe pneumonia characterized by a non-resolving neutrophilia and hyperinflammation culminating in development of sepsis. We have recently shown a protective role of C-type lectin receptor Clec4d in pneumonic infection with KPn. The Clec4d-/- mice are highly susceptible to an otherwise sublethal KPn infection and exhibit severe lung pathology with massive accumulation of neutrophils their lungs. Our preliminary results show that this excessive neutrophilia is also observed during sterile injury in Clec4d-/- mice indicating an important function of Clec4d in neutrophil clearance. Concomitantly, Clec4d-/- neutrophils, while fully capable of antimicrobial functions such as phagocytosis of bacteria and extracellular trap formation, are not efficiently efferocytized by macrophages, thus modulating the tissue reparative phenotype of macrophages and neutrophil homeostasis. Based on these observations, we hypothesized that Clec4d plays a protective role in pneumonic sepsis by facilitating neutrophil turnover which extinguishes inflammation. To elucidate the mechanism of protective function of Clec4d in this exploratory grant, we are proposing to:
Aim 1 : establish the role of Clec4d in regulating efferocytosis in-vitro and in-vivo during KPn infection;
and Aim 2 : To determine functional significance of Clec4d-mediated efferocytosis in resolution of inflammation and control of neutrophilia. The successful completion of these studies will improve our understanding of the role of innate immune components in resolution of inflammation and lead to future in-depth studies to understand the mechanistic underpinnings. This will have implications in finding successful therapies for various immune disorders such as sepsis as well as acute and chronic lung diseases, where unbridled inflammation is the root cause of disease.
Sepsis resulting from Lung infections from Gram-negative bacteria represents substantial health care burden, owing to increasing antibiotic resistance of these pathogens. In this scenario an understanding of regulation of body?s immune mechanisms can offer alternative strategies to control these infections. Unbirdled inflammation caused by a defect in body?s ability to return to homeostatic state after the initial trigger is cleared, is the underlying cause of several inflammatory diseases, including sepsis. The studies in this proposal will help understand the role of innate immune molecules in minimizing the inflammation and excessive tissue damage. This can also offer therapeutic options for a board spectrum of inflammatory diseases, where over activation of immune response is the cause of disease development.
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