Mast"cells"(MCs)"are"derived"from"bone"marrow"pluripotent"hematopoietic" stem" cells" and" are" located" in" close" proximity" to" the" external" environment." MCs" expresses"several"receptors"on"their"surface"such"as"the"high"affinity"IgE"receptor" (Fc!RI)"and"G"ProteinECoupled"Receptors"(GPCRs)."MRGPRX2"is"a"GPCR,"which" consists"of"seven"transmembrane"domains"and"is"expressed"exclusively"in"MCs" but" no" other" immune" cells." This" receptor" is" activated" by" multiple" amphipathic" ligands" including" neuropeptides," US" Food" and" Drug" Administration" (FDA)E approved"peptidergic"drugs"and"host"defense"peptides"such"as"LL_37."HDPs"also" known" as" antimicrobial" peptides" (AMPs)" have" been" investigated" in" depth" as" an" alternative"to"overcome"antibiotic"resistance"crisis."However,"their"susceptibility"to" degradation,"cytotoxicity"and"high"production"expenses"have"limited"their"use."To" overcome" these" limitations," nonEpeptide" small" molecule" HDP" mimetics" (smHDPMs)" that" structurally" resemble" the" AMPs" properties" but" have" better" stability"and"less"cytotoxicity"have"been"developed."We"utilized"five"smHDPMs"and" found" that" these" compounds" demonstrated" its" ability" to" activate" MCs" via" MRGPRX2."This"raises"an"interesting"possibility"that"its"function"as"antimicrobial" agent"could"be"as"a"result"of"harnessing"MCs"host"defense"functions"beside"their" antimicrobial"activities."" MCs" can" also" participate" in" chronic" inflammatory" diseases" when" innate" immunity" is" dysregulated." Rosacea" is" a" chronic" skin" disease" that" is" common" among"middle"aged"Caucasians."Human"rosacea"skin"samples"exhibited"higher" 3 number"of"MCs"compared"to"normal"subjects."AMP"LL37"and"neuropeptide"(NP)" substance"P"(SP)"are"upregulated"in"rosacea."LL37"and"SP"activate"MCs"through" MRGPRX2"in#vitro.#Utilizing"Mrgprb2"knockout"mice"(Mrgprb2E/E)"we"demonstrated" a" reduction" in" erythema" presentation," inflammatory" cell" recruitment," MMP+9" and" CXCL+2"mRNA"expression"compared"to"WT"mice"following"intradermal"injection" of" LLE37" and" SP" to" rosacea" model." Calcium" signaling" is" essential" for" MC" degranulation" and" function." In" this" dissertation" we" present" an" evidence" that" STIM1/Orai1" plays" an" important" role" in" MRGPRX2" mediated" calcium" influx" and" mediators"release"when"stimulated"with"LLE37"and"SP."" Moreover,"this"dissertation"showed"naturally"occurring"missense"mutations" of" MRGPRX2" both" within" and" outside" the" receptor’s" predicted" ligand" binding" pocket" (G165E," D184H," W243R" and" H259Y)" renders" it" unresponsive" neuropeptides," HDPs" and" peptidergic" drugs" for" MC" degranulation." Thus," individuals" harboring" these" mutations" may" develop" resistance" to" drugEinduced" allergic"reactions"and"rosacea"but"may"display"increased"susceptibility"to"microbial" infection.""