Cytokine overproduction and crosslinker hypersensitivity are unlinked in Fanconi anemia macrophages

[摘要] TheFanconianemiaproteinsparticipateinacanonicalpathwaythatrepairscross‐linkingagent‐inducedDNAdamage.CellswithinactivatedFanconianemiagenesareuniversallyhypersensitivetosuchagents.Fanconianemia‐deficienthematopoieticstemcellsarealsohypersensitivetoinflammatorycytokines,and,asimportantly,FanconianemiamacrophagesoverproducesuchcytokinesinresponsetoTLR4andTLR7/8agonists.WequestionedwhetherTLR‐inducedDNAdamageistheprimarycauseofaberrantlyregulatedcytokineproductioninFanconianemiamacrophagesbyquantifyingTLRagonist‐inducedTNF‐αproduction,DNAstrandbreaks,crosslinker‐inducedchromosomalbreakage,andFanconianemiacorecomplexfunctioninFanconianemiacomplementationgroupC‐deficienthumanandmurinemacrophages.AlthoughbothM1andM2polarizedFanconianemiacellswerepredictablyhypersensitivetomitomycinC,onlyM1macrophagesoverproducedTNF‐αinresponsetoTLR‐activatingsignals.DNAdamagingagentsalonedidnotinduceTNF‐αproductionintheabsenceofTLRagonistsinwild‐typeorFanconianemiamacrophages,andmitomycinCdidnotenhanceTLRresponsesineithernormalorFanconianemiacells.TLR4andTLR7/8activationinducedcytokineoverproductioninFanconianemiamacrophages.Also,althoughTLR4activationwasassociatedwithinduceddoublestrandbreaks,TLR7/8activationwasnot.ThatDNAstrandbreaksandchromosomebreaksareneithernecessarynorsufficienttoaccountfortheoverproductionofinflammatorycytokinesbyFanconianemiacellssuggeststhatnoncanonicalanti‐inflammatoryfunctionsofFanconianemiacomplementationgroupCcontributetotheaberrantmacrophagephenotypeandsuggeststhatsuppressionofmacrophage/TLRhyperreactivitymightpreventcytokine‐inducedstemcellattritioninFanconianemia...

[学科分类] 生理学

[关键词] DNA damage;TLR;TNF‐α