Background: Macrophages are heterogenous phagocytic cells with an important role in the innate immunity. They are, also, significant contributors in the adaptive immune system. Macrophages are the most abundant immune cells in the lung during allergic asthma, which is the most common chronic respiratory disease of both adults and children. Macrophages activated by Th1 cells are known as M1 macrophages while those activated by IL-4 and IL-13 are called alternatively activated macrophages (AAM) or M2 cells. AAM are subdivided into four distinct subtypes (M2a, M2b, M2c and M2d), depending on the nature of inducing agent and the expressed markers. Body: IL-4 is the major effector cytokine in both alternative activation of macrophages and pathogenesis of asthma. Thus, the role of M2a macrophages in asthma is a major concern. However, this is controversial. Therefore, further studies are required to improve our knowledge about the role of IL-4-induced macrophages in allergic asthma, through precisive elucidation of the roles of specific M2a proteins in the pathogenesis of asthma. In the current review, we try to illustrate the different functions of M2a macrophages (protective and pathogenic roles) in the pathogenesis of asthma, including explanation of how different M2a proteins and markers act during the pathogenesis of allergic asthma. These include surface markers, enzymes, secreted proteins, chemokines, cytokines, signal transduction proteins and transcription factors. Conclusions: AAM is considered a double-edged sword in allergic asthma. Finally, we recommend further studies that focus on increased selective expression or suppression of protective and pathogenic M2a markers.

High mobility group box 1 (HMGB1) is an alarmin actively secreted by immune cells and passively released by necrotic nonimmune cells. HMGB1 has been implicated in both cardiac contractile dysfunction and the lethality associated with sepsis/endotoxemia. The aim of the current study was to assess whether viable cardiomyocytes could produce HMGB1 and whether HMGB1 can affect myocardial contractility. LPS was used as a model of sepsis/endotoxemia in mice and isolated cardiac myocytes. LPS increased myocardial expression of HMGB1 in vivo (immunohistochemistry) and production and secretion of HMGB1 by viable cardiac myocytes in vitro (Western). LPS increased the phosphorylation status of PI3Kgamma in cardiac myocytes, an effect not observed in TLR4(-/-) myocytes. Genetic (PI3Kgamma(-/-)) or pharmacologic (AS605240) blockade of PI3Kgamma ameliorated the LPS-induced 1) cardiomyocyte production and secretion of HMGB1 in vitro and 2) HMGB1 expression in the myocardium in vivo. The LPS-induced depression of myocardial contractility was prevented by the HMGB1 antagonist, A-box. Genetic (PI3Kgamma(-/-)) or pharmacologic (AS605240) blockade of PI3Kgamma ameliorated the LPS-induced decrease in myocardial contractility. No evidence of inflammatory infiltrate was noted in any of the in vivo studies. The findings of the current study indicate that 1) LPS can induce HMGB1 secretion by viable cardiac myocytes through a TLR4/PI3Kgamma signaling pathway, and 2) HMGB1 plays a role in the LPS-induced myocardial contractile dysfunction. The results of the current study also have broader implications (i.e., that viable parenchymal cells, such as cardiac myocytes, participate in the alarmin response).

Newly identified nuocytes or group 2 innate lymphoid cells (ILC2s) play an important role in Th2 cell mediated immunity such as protective immune responses to helminth parasites, allergic asthma, and chronic rhinosinusitis. However, the contributions of ILC2s in the occurrence and development of cancer remain unknown. Our previous study found that there was a predominant Th2 phenotype in patients with gastric cancer. In this study, the ILC2s related genes or molecules in PBMC from patients with gastric cancer were measured, and the potential correlation between them was analyzed. The expression levels of RORα, GATA3, T1/ST2, IL-17RB, CRTH2, IL-33, IL-5, and IL-4 mRNA were significantly increased in patients, but no significant changes were found in ICOS, CD45, and IL-13 expression, and there was a positive correlation between RORα or IL-13 and other related factors, such as ICOS and CD45. The increased frequency of ILC2s was also found in PBMC of patients by flow cytometry. In addition, the mRNA of Arg1 and iNOS were also significantly increased in patients. These results suggested that there are polarized ILC2s in gastric cancer patients which might contribute to immunosuppressive microenvironment and closely related to the upregulation of MDSCs and M2 macrophages.

High-mobility group box 1 (HMGB1) is a nuclear protein that has been implicated in the myocardial inflammation and injury induced by ischemia-reperfusion (I/R). The purpose of the present study was to assess the role of HMGB1 in myocardial apoptosis induced by I/R. In vivo, myocardial I/R induced an increase in myocardial HMGB1 expression and apoptosis. Inhibition of HMGB1 (A-box) ameliorated the I/R-induced myocardial apoptosis. In vitro, isolated cardiac myocytes were challenged with anoxia-reoxygenation (A/R; in vitro correlate to I/R). A/R-challenged myocytes also generated HMGB1 and underwent apoptosis. Inhibition of HMGB1 attenuated the A/R-induced myocyte apoptosis. Exogenous HMGB1 had no effect on myocyte apoptosis. However, inhibition of HMGB1 attenuated myocyte TNF-α production after the A/R was challenged; surprisingly, HMGB1 itself did not induce myocyte TNF-α production. Exogenous TNF-α induced a moderate proapoptotic effect on the myocytes, an effect substantially potentiated by coadministration of HMGB1. It is generally accepted that apoptosis induced by TNF-α is regulated by the balance of activation of c-Jun NH(2)-terminal kinase (JNK) and NF-κB. Indeed, in the present study, TNF-α increased the phosphorylation status of JNK and p65, a subunit of NF-κB; HMGB1 greatly potentiated TNF-α-induced JNK phosphorylation. Furthermore, inhibition of JNK (SP-600125) prevented the myocyte apoptosis induced by a TNF-α/HMGB1 cocktail. Finally, A/R increased HMGB1 production in both wild-type and toll-like receptor 4-deficient myocytes; however, deficiency in toll-like receptor 4 diminished A/R-induced myocyte apoptosis, TNF-α, and JNK activation. Our results indicate that myocyte-derived HMGB1 and TNF-α work in concert to promote I/R-induced myocardial apoptosis through JNK activation.