Regulation of Langerhans cell functions in a hypoxic environment

Abstract

Current treatments for allergic asthma primarily ameliorate symptoms rather than inhibit disease progression. Regulating the excessive T helper type 2 (Th2) responses may prevent asthma exacerbation. In this study, we investigated the protective effects of Ad5-gsgAM, an adenovirus vector carrying two mycobacterial antigens Ag85A and Mtb32, against allergic asthma. Using an ovalbumin (OVA)-induced asthmatic mouse model, we found that Ad5-gsgAM elicited much more Th1-biased CD4 + T and CD8 + T cells than bacillus CalmetteGuérin (BCG). After OVA challenge, Ad5-gsgAM-immunized mice showed significantly lowered airway inflammation in comparison with mice immunized with or without BCG. Total serum immunoglobulin E and pulmonary inducible-nitric-oxide-synthase were efficiently reduced. The cytokine profiles in bronchial-alveolar-lavage-fluids (BALFs) were also modulated, as evidenced by the increased level of interferon-γ (IFN-γ) and the decreased level of interleukin (IL)-4, IL-5, and IL-13. Anti-inflammatory cytokine IL-10 was sharply increased, whereas pro-inflammatory cytokine IL-33 was significantly decreased. Importantly, exogenous IL-33 abrogated the protective effects of Ad5-gsgAM, revealing that the suppression of IL-33/ST2 axis substantially contributed to protection against allergic inflammation. Moreover, regulatory T cells were essential for regulating aberrant Th2 responses as well as IL-33/ST2 axis. These results suggested that modulating the IL-33/ST2 axis via adenovirus-vectored mycobacterial antigen vaccination may provide clinical benefits in allergic inflammatory airways disease. Key messages•Ad5-gsgAM elicits Th1 responses and suppresses Th2-mediated allergic asthma in mice.•Ad5-gsgAM inhibits IL-33/ST2 axis by reducing IL-33 secretion but not ILC2 recruiting.•Treg is essential for modulating Th2 responses and IL-33/ST2 axis by Ad5-gsgAM.

Regulation of Human Macrophage M1–M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1

“…Furthermore, the evidence that secretion of IL-12, the main Th1-priming cytokine ( 69 ), and CCL18, a specific chemoattractant and activating cytokine for naive T cells and iDCs ( 70 ), was inhibited under hypoxia in M1-polarized Mf raises the possibility that their Th1-priming ability is impaired under hypoxic conditions, and further investigations are underway to address this hypothesis. Interestingly, these results confirm and extend our earlier evidence in Mn-derived Langerhans cell showing that hypoxia inhibits their expression of T cell costimulatory molecules and impairs their stimulatory activity on naive T cells ( 42 ), but differ from previous findings in Mn-derived DCs that demonstrated CD80 and CD86 molecule overexpression upon differentiation under conditions of reduced oxygenation ( 41 , 68 , 71 ). Taken together, these findings strongly suggest that hypoxia can differentially modulate the T cell stimulatory activity of distinct Mn lineage cell subsets.…”

“…Noteworthily, TREM-1 mRNA and membrane-bound receptor levels, as well as release of its soluble form detectable in several inflammatory disorders ( 56 ), were consistently and significantly increased upon Mf differentiation under chronic hypoxia. This evidence, together with previous observation showing TREM-1 upregulation in primary Mn in response to hypoxia ( 52 , 74 ) and inducibility in iDCs, mDCs, and Langerhans cells ( 40 – 42 ), is consistent with a role for hypoxia as a trigger of TREM-1 expression, indicating that hypoxic stimulation can overcome TREM-1 developmental downregulation, and highlights the relevance of TREM-1 as a common marker of distinct Mn lineage cell populations in a hypoxic environment.…”

“…In this study, we investigated the impact of a hypoxic environment reflecting that occurring in diseased tissues on the polarization of human Mn-derived Mf. We present data showing that development under hypoxic conditions (1% O 2 ) skews Mf polarization toward a M2 phenotype and characterize a previously unrecognized role for the triggering receptor expressed on myeloid cells (TREM)-1, a member of the Ig superfamily of immunoregulatory receptors ( 38 , 39 ) that we have recently identified as a new hypoxia-inducible gene in Mn-derived DCs ( 40 – 42 ), as a critical determinant of hypoxic M2-to-M1 reprogramming. Molecules associated with M1 polarization are being actively sought as potential diagnostic tools and therapeutic targets in chronic inflammatory conditions, including oligoarticular juvenile idiopatic arthritis (OJIA), the most common pediatric chronic rheumatic disease characterized by extensive and persistent synovial Mn cell infiltration and hypoxia ( 5 , 43 ).…”

Biological approaches for hypertrophic scars

“…Regarding immune cells, it was reported that specialized dendritic cells, such as Langerhans cells (LCs), reside in epidermis play the key role in the forming of HSs . In aberrant wound healing, LCs stimulated naive T cell responses, and identify the triggering receptor expressed on myeloid (TREM)‐1, a member of the Ig immunoregulatory receptor family, infiltrating hypoxic areas of active HSs, pointing to the pathogenic role in wound repair disorders . Besides, it has been found that there is a correlation of NK cell, T‐cell, and scarring .…”

“…185 In aberrant wound healing, LCs stimulated naive T cell responses, and identify the triggering receptor expressed on myeloid (TREM)-1, a member of the Ig immunoregulatory receptor family, infiltrating hypoxic areas of active HSs, pointing to the pathogenic role in wound repair disorders. 186 Besides, it has been found that there is a correlation of NK cell, T-cell, and scarring. 187 For example, NK cells inhibit the progression of liver fibrosis through targeting and clearing the hepatic astrocytes directly which secrete ECM, suggesting an important role in antifibrosis.…”