Tissue-resident macrophages exacerbate lung injury after remote sterile damage

Remote organ injury,which is a common secondary complication of sterile tissue damage,is a major cause of poor prognosis and is difficult to manage.Here,we report the critical role of tissue-resident macrophages in lung injury after trauma or stroke through the inflammatory response.We found that depleting tissue-resident macrophages rather than disrupting the recruitment of monocyte-derived macrophages attenuated lung injury after trauma or stroke.Our findings revealed that the release of circulating alarmins from sites of distant sterile tissue damage triggered an inflammatory response in lung-resident macrophages by binding to receptor for advanced glycation end products(RAGE)on the membrane,which activated epidermal growth factor receptor(EGFR).Mechanistically,ligand-activated RAGE triggered EGFR activation through an interaction,leading to Rab5-mediated RAGE internalization and EGFR phosphorylation,which subsequently recruited and activated P38;this,in turn,promoted RAGE translation and trafficking to the plasma membrane to increase the cellular response to RAGE ligands,consequently exacerbating inflammation.Our study also showed that the loss of RAGE or EGFR expression by adoptive transfer of macrophages,blocking the function of RAGE with a neutralizing antibody,or pharmacological inhibition of EGFR activation in macrophages could protect against trauma-or stroke-induced remote lung injury.Therefore,our study revealed that targeting the RAGE-EGFR signaling pathway in tissue-resident macrophages is a potential therapeutic approach for treating secondary complications of sterile damage.

Tissue-resident lymphocytes: from adaptive to innate immunity

Efficient immune responses against invading pathogens often involve coordination between cells from both the innate and adaptive immune systems.For multiple decades,it has been believed that CD8+memory T cells and natural killer(NK)cells constantly and uniformly recirculate.Only recently was the existence of noncirculating memory T and NK cells that remain resident in the peripheral tissues,termed tissue-resident memory T(TRM)cells and tissue-resident NK(trNK)cells,observed in various organs owing to improved techniques.TRM cells populate a wide range of peripheral organs,including the skin,sensory ganglia,gut,lungs,brain,salivary glands,female reproductive tract,and others.Recent findings have demonstrated the existence of TRM in the secondary lymphoid organs(SLOs)as well,leading to revision of the classic theory that they exist only in peripheral organs.trNK cells have been identified in the uterus,skin,kidney,adipose tissue,and salivary glands.These tissue-resident lymphocytes do not recirculate in the blood or lymphatic system and often adopt a unique phenotype that is distinct from those of circulating immune cells.In this review,we will discuss the recent findings on the tissue residency of both innate and adaptive lymphocytes,with a particular focus on CD8+memory T cells,and describe some advances regarding unconventional T cells(invariant NKT cells,mucosal-associated invariant T cells(MAIT),andγδT cells)and the emerging family of trNK cells.Specifically,we will focus on the phenotypes and functions of these subsets and discuss their implications in anti-viral and anti-tumor immunity.

Tissue-resident memory T cells and their biological characteristics in the recurrence of inflammatory skin disorders

The skin is the largest organ of the body.The establishment of immunological memory in the skin is a crucial component of the adaptive immune response.Once naive T cells are activated by antigen-presenting cells,a small fraction of them differentiate into precursor memory T cells.These precursor cells ultimately develop into several subsets of memory T cells,including central memory T(TCM)cells,effector memory T(TEM)cells,and tissue resident memory T(TRM)cells.TRM cells have a unique transcriptional profile,and their most striking characteristics are their long-term survival(longevity)and low migration in peripheral tissues,including the skin.Under physiological conditions,TRM cells that reside in the skin can respond rapidly to pathogenic challenges.However,there is emerging evidence to support the vital role of TRM cells in the recurrence of chronic inflammatory skin disorders,including psoriasis,vitiligo,and fixed drug eruption,under pathological or uncontrolled conditions.Clarifying and characterizing the mechanisms that are involved in skin TRM cells will help provide promising strategies for reducing the frequency and magnitude of skin inflammation recurrence.Here,we discuss recent insights into the generation,homing,retention,and survival of TRM cells and share our perspectives on the biological characteristics of TRM cells in the recurrence of inflammatory skin disorders.

Tissue-resident natural killer cells in the livers

Nature killer(NK) cells are important lymphocytes of the innate immune system,well known for their pivotal roles in immune surveillance and defense against tumor and virus-infected cells.Current studies have revealed that NK cells are not a homogeneous population,but instead consist of distinct subsets with diverse characteristics.As an organ with predominant innate immunity,the liver is enriched with NK cells,among which two distinct NK cell subsets have recently been identified:conventional NK(cNK)cells and tissue-resident NK(trNK) cells.Liver trNK cells are markedly different from cNK cells in many aspects,representing a new lineage of innate lymphoid cell(ILC) family.Here,we summarize the phenotypic and functional features of liver trNK cells,and review current knowledge regarding developmental pathway of liver trNK cells.We also overview recent advances in human liver trNK cells and discuss the striking shared hallmarks of trNK cells in different tissues.

Local heroes or villains:tissue-resident memory T cells in human health and disease

Tissue-resident memory T(T_(RM))cells are increasingly associated with the outcomes of health and disease.T_(RM) cells can mediate local immune protection against infections and cancer,which has led to interest in T_(RM) cells as targets for vaccination and immunotherapies.However,these cells have also been implicated in mediating detrimental pro-inflammatory responses in autoimmune skin diseases such as psoriasis,alopecia areata,and vitiligo.Here,we summarize the biology of T_(RM) cells established in animal models and in translational human studies.We review the beneficial effects of T_(RM) cells in mediating protective responses against infection and cancer and the adverse role of T_(RM) cells in driving pathology in autoimmunity.A further understanding of the breadth and mechanisms of T_(RM) cell activity is essential for the safe design of strategies that manipulate T_(RM) cells,such that protective responses can be enhanced without unwanted tissue damage,and pathogenic T_(RM) cells can be eliminated without losing local immunity.

Defining newly formed and tissue-resident bone marrow-derived macrophages in adult mice based on lysozyme expression

Tissue-resident macrophages are derived from different precursor cells and display different phenotypes.Reconstitution of the tissue-resident macrophages of inflamed or damaged tissues in adults can be achieved by bone marrow-derived monocytes/macrophages.Using lysozyme(Lysm)-GFP-reporter mice,we found that alveolar macrophages(AMs),Kupffer cells,red pulp macrophages(RpMacs),and kidney-resident macrophages were Lysm-GFP^(−),whereas all monocytes in the fetal liver,adult bone marrow,and blood were Lysm-GFP^(+).Donor-derived Lysm-GFP^(+)resident macrophages gradually became Lysm-GFP−in recipients and developed gene expression profiles characteristic of tissue-resident macrophages.Thus,Lysm may be used to distinguish newly formed and long-term surviving tissue-resident macrophages that were derived from bone marrow precursor cells in adult mice under pathological conditions.Furthermore,we found that Irf4 might be essential for resident macrophage differentiation in all tissues,while cytokine and receptor pathways,mTOR signaling pathways,and fatty acid metabolic processes predominantly regulated the differentiation of RpMacs,Kupffer cells,and kidney macrophages,respectively.Deficiencies in ST2,mechanistic target of rapamycin(mTOR)and fatty acid-binding protein 5(FABP5)differentially impaired the differentiation of tissue-resident macrophages from bone marrow-derived monocytes/macrophages in the lungs,liver,and kidneys.These results indicate that a combination of shared and unique signaling pathways coordinately shape tissue-resident macrophage differentiation in various tissues.

Tissue-resident macrophages: from zebrafish to mouse

Tissue-resident macrophages(TRMs),generally found in tissues under normal physiological conditions,play crucial roles not only in immunity but also in tissue development and homeostasis.Because of their diverse functions,dysregulation of their development and function has been implicated in many human disorders.In the past decade,a great deal of extensive studies have been conducted in various model organisms with cutting-edge technologies to explore the origin and function of TRMs.In this review,we summarize the recent findings on TRMs in mouse and zebrafish and compare the similarity/differences between these two species.

Tissue-resident memory-like ILCs: innate counterparts of TRM cells

Innate lymphoid cells(ILCs)are defined as lymphocytes that lack RAG recombinase and do not express diverse antigen receptors;however,recent studies have revealed the adaptive features of ILCs.Mouse cytomegalovirus(MCMV)-and cytokine-induced memory natural killer(NK)cells circulate in the blood and are referred to as conventional memory NK cells.In contrast,virusand hapten-induced memory NK cells,hapten-induced memory ILC1s,and cytokine-induced memory-like ILC2s exhibit long-term residency in the liver or lung,and are referred to as tissue-resident memory ILCs.Considering their similar migration patterns and memory potential,tissue-resident memory ILCs could be regarded as innate counterparts of resident memory T(T r m)cells.Both tissue-resident memory ILCs and TRM cells share common characteristics in terms of dynamics,phenotype,and molecular regulation.The emergence of ILC memory expands the basic biology of ILCs and prompts us to re-examine their functions in disease progression.This review discusses the evidence supporting tissue-resident memory NK cells and other memory ILC subsets,compares them with TRM cells,and highlights key unsolved questions in this emerging field.

The heterogeneity of tumor-associated macrophages and strategies to target it

Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.

Advancement in regional immunity and its clinical implication

Organs in our body have formed their own unique immune surveillance system that is finely tuned by in situ milieu. Sequestrated tissue-resident immune cells differ from their counterparts in circulation and participate in tissue physiological activities and the maintenance of local homeostasis. Dysregulation of regional immunity leads to organ-specific inflammatory injuries. Here we review the recent developments in the field of tissue-resident immune cells and organ-specific regional immunity, and discuss their clinical implication.