Eosinophil-derived chemokine(hCCL 15/23,mCCL6)interacts with CCR1 to promote eosinophilic airway inflammation

Eosinophils are terminally differentiated cells derived from hematopoietic stem cells(HSCs)in the bone marrow.Several studies have confirmed the effective roles of eosinophils in asthmatic airway pathogenesis.However,their regulatory functions have not been well elucidated.Here,increased C-C chemokine ligand 6(CCL6)in asthmatic mice and the human orthologs CCL15 and CCL23 that are highly expressed in asthma patients are described,which are mainly derived from eosinophils.Using Cc/6 knockout mice,further studies revealed CCL6-dependent allergic airway inflammation and committed eosinophilia in the bone marrow following ovalbumin(OVA)challenge and identified a CCL6-CCR1 regulatory axis in hematopoietic stem cells(HSCs).Eosinophil differentiation and airway inflammation were remarkably decreased by the specific CCR1 antagonist BX471.Thus,the study identifies that the CCL6-CCR1 axis is involved in the crosstalk between eosinophils and HSCs during the development of allergic airway inflammation,which also reveals a potential therapeutic strategy for targeting G protein-coupled receptors(GPCRs)for future clinical treatment of asthma.

A prodrug nanoplatform via esterification of STING agonist and IDO inhibitor for synergistic cancer immunotherapy

Cancer immunotherapy has made significant progress in the last few decades,revolutionizing oncology.However,low patient response rates and potential immune-related adverse events continue to be major clinical challenges.Cancer nanomedicine,by virtue of its regulated delivery and modular flexibility,has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy.In this study,we developed tumor microenvironment(TME)responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner,while simultaneously reducing immune-related side effects.We synthesized the TME responsive prodrug by coupling MSA-2,a stimulator of interferon genes(STING)agonist,and NLG-919,an indoleamine 2,3 dioxygenase(IDO)inhibitor.The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability.By synthesizing a TME responsive prodrug,we aim to explore the therapeutic efficacy of combined regimen(STING agonist and IDO inhibitor)for cancer,and reduce the unwanted side effects of STING agonism on normal tissues.Free prodrug and nanoparticles were characterized by mass spectrometry,dynamic light scattering(DLS),and transmission electron microscopy(TEM).Following that,we investigated the tumor accumulation,anti-tumor activity,and toxicity in vitro and in vivo.Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment.The TME responsive nanomedicine provided an effective tool for precise targeting,promoting antitumor immunity,and efficient tumor growth inhibition with safety.Outcomes of this study may have implications for future clinical trials.

LPS-induced mitochondrial DNA synthesis and release facilitate RAD50-dependent acute lung injury

Dear Editor,ATP-binding cassette(ABC)-ATPase(RAD50),together with meiotic recombination 11 homolog 1(MRE11)subunits,to form MRE11-RAD50 complex,plays important roles in recognition of double-stranded DNA(dsDNA)and initiation of consequent inflammatory cascade1.Acute lung injury(ALI)and acute respiratory destress syndrome(ARDS)are systemic uncontrolled inflammation and life-threatening.However,the function of the DNA sensor in ALI/ARDS remains poorly defined.Here we investigated functions of RAD50 using mouse primary macrophages and conditionally RAD50 knockout mice in vitro and in a lipopolysaccharide(LPS)-induced lung injury model.