Lysosomal acid lipase is critical for myeloid-derived suppressive cell differentiation, development, and homeostasis

Lysosomal acid lipase （LAL） cleaves cholesteryl esters （CE） and triglycerides （TG） to generate cholesterol and free fatty acid in lysosomes of cells. The down-stream metabolic products of fatty acids are ligands for activation of peroxisome proliferator-activated re-ceptor gamma （PPARγ）. Accumulation of CEs and TGs is resulted from lack of functional LAL in lysosomes of cells, especially in myeloid cells. One characteristic phenotype in LAL knock-out （ lal-/- ） mice is systemic elevation of myeloid-derived suppressive cells （MDSCs）. MDSCs infltrate into multiple distal organs, alter T cell development, and suppress T cell proliferation and lym-phokine production in lal-/- mice, which lead to severe pathogeneses in multiple organs. The gene transcrip-tional profle analysis in MDSCs from the bone marrow has identified multiple defects responsible for MDSCs malformation and malfunction in lal-/- mice, including G protein signaling, cell cycles, glycolysis metabolism, mitochondrial bioenergetics, mTOR pathway etc. In a sep-arate gene transcriptional profle analysis in the lung of lal-/- mice, matrix metalloproteinase 12 （MMP12） and apoptosis inhibitor 6 （Api6） are highly overexpressed due to lack of ligand synthesis for PPARγ. PPARγ nega-tively regulates MMP12 and Api6. Blocking the PPAR signaling by overexpression of a dominant negative PPARγ （dnPPARγ） form, or overexpressing MMP12 or Api6 in myeloid or lung epithelial cells in inducible transgenic mouse models results in elevated MDSCs and infammation-induced tumorigenesis. These stud-ies demonstrate that LAL and its downstream effectors are critical for MDSCs development, differentiation and malfunction.

Microenvironmental influences on T cell immunity in cancer and inflammation

T cell metabolism is dynamic and highly regulated.While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns,the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways.T cells must function in a wide variety of tissue settings,and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance.Both in inflamed and cancer tissues,a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity.These include fever and increased temperatures,depletion of critical micro and macro-nutrients,and accumulation of inhibitory waste products.Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity.

Cytokine regulation of immune tolerance

The immune system provides defenses against invading pathogens while maintaining immune tolerance to self-antigens.This immune homeostasis is harmonized by the direct interactions between immune cells and the cytokine environment in which immune cells develop and function.Herein,we discuss three non-redundant paradigms by which cytokines maintain or break immune tolerance.We firstly describe how anti-inflammatory cytokines exert direct inhibitory effects on immune cells to enforce immune tolerance,followed by discussing other cytokines that maintain immune tolerance through inducing CD_(4)^(+) Foxp_(3)^(+) regulatory T cells(Tregs),which negatively control immune cells.Interleukin(IL)-2 is the most potent cytokine in promoting the development and survival of Tregs,thereby mediating immune tolerance.IL-35 is mainly produced by Tregs,but its biology function remains to be defi ned.Finally,we discuss the actions of proinflammatory cytokines that breach immune tolerance and induce autoimmunity,which include IL-7,IL-12,IL-21,and IL-23.Recent genetic studies have revealed the role of these cytokines(or their cognate receptors)in susceptibility to autoimmune diseases.Taken together,we highlight in this review the cytokine regulation of immune tolerance,which will help in further understanding of human diseases that are caused by dysregulated immune system.

Myeloid-specific expression of Stat3C results in conversion of bone marrow mesenchymal stem cells into alveolar type Ⅱ epithelial cells in the lung

Bone marrow mesenchymal stem cells (BMSCs) and myeloid lineage cells originate from the bone marrow, and influence each other in vivo. To elucidate the mechanism that controls the interrelationship between these two cell types, the signaling path- way of signal transducer and activator of transcription 3 (Stat3) was activated by overexpressing Stat3C in a newly established c-fms-rtTA/(TetO)7-CMV-Stat3C bitransgenic mouse model, In this system, Stat3C-Flag fusion protein was overexpressed in myeloid lineage cells after doxycycline treatment. Stat3C overexpression induced systematic elevation of macrophages and neutrophils in multiple organs. In the lung, tissue neoplastic pneumocyte proliferation was observed. After in vitro cultured hSP-B 1.5-kb lacZ BMSCs were injected into the bitransgenic mice, BMSCs were able to repopulate in multiple organs, self-renew in the bone marrow and spleen, and convert into alveolar type II epithelial cells. The bone marrow transplantation study indicated that increases of myeloid lineage cells and BMSC-AT II cell conversion were due to malfunction of myeloid progenitor cells as a result of Stat3C overexpression. The study supports the concept that activation of the Stat3 pathway in myeloid cells plays an important role in BMSC function, including homing, repopulating and converting into residential AT II epithelial cells in the lung.

Retinoic acid signaling acts as a rheostat to balance Treg function

Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses.Under certain inflammatory conditions,Tregs can lose their lineage stability and function.Previous studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and stability.However,it is unknown how RA receptor signaling in Tregs influences these processes in vivo.Herein,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T cells.Despite the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor function.Furthermore,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic proteins.Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist.Unexpectedly,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and autoimmunity.The loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive capacity.Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling.Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.