The NF-kappaB modulator PDLIM2 as an intrinsic checkpoint of alveolar macrophages critical for lung innate immunity, inflammation and diseases - Abstract Pneumonia is a common cause of mortality, particularly in patients with lung cancer or lung diseases. Alveolar macrophages (AMs), the primary phagocytes that serve as the major sentinels in the lung, have been believed to be the main culprits of the fatal pathogenesis. However, it remains largely unknown how these key innate immune cells are transformed to promote lung cancer or lung diseases and to increase vulnerability to infection. In fact, it is still largely unknown how AMs are armed with the strong ability to clear pathogens and mutated cells while simultaneously maintaining immune tolerance within the lung under normal conditions. To address those scientifically and clinically important issues, we have recently identified a unique characteristic of AMs in the inherent expression of the immune checkpoint PD-L1 and a previously unknown role of PD-L1, via cis- interaction with CD80, in rendering AMs highly phagocytic. PD-L1 also arms AMs with a super T-cell suppressive ability, indicating an innovative mechanism by which AMs provide optimal protective immunity and tolerance within the lung. Furthermore, we have identified the PDZ-LIM domain-containing protein PDLIM2, a tumor suppressor recently uncovered by us, as a new determinant of AMs required for CD80 induction and AM phagocytosis. By promoting degradation of the master pro-inflammatory transcription factors NF-B RelA and STAT3 in the nucleus, PDLIM2 is also required to restrict monocyte pulmonary recruitment and differentiation into AMs and to inhibit AM inflammatory activation, thereby limiting inflammation. Amazingly, selective deletion of PDLIM2 in AMs and myeloid cells alone is sufficient to induce lung cancer in mice and makes animals more vulnerable to deaths by the bacterial endotoxin LPS. On the other hand, PDLIM2 is repressed in the AMs of patients with lung cancer, chronic obstructive pulmonary disease (COPD), and interstitial lung diseases (ILDs), and this repression is associated with disease severity and poor patient survival. Of note, PDLIM2 repression in AMs is induced both in vivo and ex vivo by smoking, the most predominant cause of lung cancer and diseases and a prominent risk factor for pneumonia and pneumonia death. Based on these original new discoveries, we hypothesize that PDLIM2 repression in AMs not only promotes lung cancer and lung diseases but also increases vulnerability to lung infection. To test the hypothesis, we will determine the physiological and pathophysiological significance and the detailed mechanisms of the novel PDLIM2/CD80/ PD- L1 signaling pathway in AM phagocytosis, immune response, and bacterial pneumonia. These studies will improve our understanding of lung innate immunity, inflammation, infection, and pathogenesis, and may reveal new therapeutic targets and approaches for better lung disease treatment.
