Twenty Novel Disease Group-Specific and 12 New Shared Macrophage Pathways in Eight Groups of 34 Diseases Including 24 Inflammatory Organ Diseases and 10 Types of Tumors

The mechanisms underlying pathophysiological regulation of tissue macrophage (M phi) subsets remain poorly understood. From the expression of 207 M phi genes comprising 31 markers for 10 subsets, 45 transcription factors (TFs), 56 immunometabolism enzymes, 23 trained immunity (innate immune memory) enzymes, and 52 other genes in microarray data, we made the following findings. (1) When 34 inflammation diseases and tumor types were grouped into eight categories, there was differential expression of the 31 M phi markers and 45 M phi TFs, highlighted by 12 shared and 20 group-specific disease pathways. (2) M phi in lung, liver, spleen, and intestine (LLSI-M phi) express higher M1 M phi markers than lean adipose tissue M phi (ATM phi) physiologically. (3) Pro-adipogenic TFs C/EBP alpha and PPAR gamma and proinflammatory adipokine leptin upregulate the expression of M1 M phi markers. (4) Among 10 immune checkpoint receptors (ICRs), LLSI-M phi and bone marrow (BM) M phi express higher levels of CD274 (PDL-1) than ATM phi, presumably to counteract the M1 dominant status via its reverse signaling behavior. (5) Among 24 intercellular communication exosome mediators, LLSI- and BM- M phi prefer to use RAB27A and STX3 than RAB31 and YKT6, suggesting new inflammatory exosome mediators for propagating inflammation. (6) M phi in peritoneal tissue and LLSI-M phi upregulate higher levels of immunometabolism enzymes than does ATM phi. (7) M phi from peritoneum and LLSI-M phi upregulate more trained immunity enzyme genes than does ATM phi. Our results suggest that multiple new mechanisms including the cell surface, intracellular immunometabolism, trained immunity, and TFs may be responsible for disease group-specific and shared pathways. Our findings have provided novel insights on the pathophysiological regulation of tissue M phi, the disease group-specific and shared pathways of M phi, and novel therapeutic targets for cancers and inflammations.