I don't remember exactly, but essentially the Pope got mad at the Venetians, probably over debts. At the time, the Pope was really well connected, and both France and Spain were looking to cut in on Venice's trading empire. The HRE wanted to reassert itself in Italy.
With Venice basically destroyed by the combined force of Europe, France emerged as the dominant power in Northern Italy. Spain consolidated itself in Southern Italy. The HRE had some peasant uprising or some shit. The Pope, naturally, took the side of (now crippled) Venice to drive France out of Italy and assert Vatican dominance.
At some point, the Pope declares a sort-of Holy War. So all of Christianity gets involved, as England, Spain, and the HRE all want some part of France.
Finally, Scotland joins France because they do that a lot to fuck with England. Milan also wants a chunk of France. Venice, sick of having to share Northern Italy, sides with France.
The wars resume a few years later, because France and Spain both want all of Italy, and the Spanish crown marries into the Habsburgs, sealing an alliance between the HRE and Spain. Florence, now a Republic, comes in against the Pope (Machiavelli actually trains the troops) and wins with a homegrown army because thousands of Swiss mercenaries have to leave when the Swiss government says Swiss can't fight other Swiss. The Pope helps the Medici return to power, allying Florence and the Papacy. The Popes then flip-flop between being pro-France and pro-Spain.
To fund the wars, the Popes ramp up indulgence sales, triggering a handful of German priests. The Habsburgs tax the nobles and the Bourbons tax the middle class, setting up the 30 Years War and the Huguenot conflicts.